Treatment of chronic hepatitis B in children
2003; Elsevier BV; Volume: 39; Linguagem: Inglês
10.1016/s0168-8278(03)00328-3
ISSN1600-0641
Autores Tópico(s)Hepatitis C virus research
Resumo1. Reasons and endpoints for therapyChronic hepatitis B (CHB) is now preventable by vaccination. In highly endemic areas vaccination campaigns, primarily addressed to infants and adolescents, have drastically reduced the prevalence of infection in these age groups [[1]Chang M.H Chen C.J Lai M.S Hsu H.M Wu T.C Kong M.S et al.Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children.N Engl J Med. 1997; 336: 1855-1859Crossref PubMed Scopus (1572) Google Scholar]. On a worldwide basis, however, the reservoir of infection is maintained by children born in areas without adequate vaccination policies, by children infected prior to vaccination campaigns and by the small percentage of cases who acquire infection despite hepatitis B virus (HBV) prophylaxis. Thus a consistent pool of chronically infected children still needs management and care.The clinical management of CHB is best approached from an understanding of the natural history of the disease. In adult patients CHB is known to carry a significant lifetime risk of cirrhosis and hepatocellular carcinoma (HCC) [[2]Beasley R.P Hwang L.-Y Overview on the epidemiology of hepatocellular carcinoma.in: Hollinger F.B Lemon S.M Margolis H Viral hepatitis and liver disease. William and Wilkins, Baltimore, MD1991: 532-535Google Scholar]. These 'hard outcomes' have strongly encouraged therapeutic investigation.In children and adolescents two major patterns of chronic HBV infection have been recognized. (1) Infection acquired at birth is usually asymptomatic and characterized by a prolonged immunotolerance phase: 85% of babies infected prior to vaccination in Taiwan were still HBeAg positive by the age of 15 years [[3]Chang M.-H Natural history of hepatitis B virus infection in children.J Gastroenterol Hepatol. 2000; 15: E16-E19Crossref PubMed Scopus (80) Google Scholar]. In the same area, prospective studies in adult patients, probably infected at birth, described a prolonged immunoclearance phase, lasting up to the age of 40 [4Liaw Y.F Tai D.I Chu C.M Chen T.J The development of cirrhosis in patients with chronic type B hepatitis: a prospective study.Hepatology. 1988; 8: 493-496Crossref PubMed Scopus (544) Google Scholar, 5Yuen M.-F Lai C.-L Natural history of chronic hepatitis B virus infection.J Gastroenterol Hepatol. 2000; 15: E20-E24Crossref PubMed Scopus (57) Google Scholar]. This phase was characterized by repeated bouts of alanine transaminase (ALT) exacerbation worsening the prognosis of liver disease. (2) The second pattern is typical of intermediate endemicity areas, where infection is preferably acquired horizontally during the first months or years of life. The tolerance phase is shorter or does not exist, and long-term studies in different countries (Italy and Spain, Alaska) have recently shown that approx. 70–85% of these children will spontaneously become inactive HBV carriers before adulthood [6Bortolotti F Jara P Crivellaro C Hierro L Cadrobbi P Frauca E et al.Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period.J Hepatol. 1998; 29: 184-190Abstract Full Text PDF PubMed Scopus (116) Google Scholar, 7McMahon B Holck P Bulkow L Snowball R.N Serologic and clinical outcome of 1536 Alaskan natives chronically infected with hepatitis B virus.Ann Intern Med. 2001; 135: 759-768Crossref PubMed Scopus (350) Google Scholar, 8Marazzi M.G Gigliotti A.R Bondi E Palumbo M Casalini Finocchio G Clinical outcome of chronic hepatitis B in children during a long term follow-up.Ital J Pediatr. 2002; 28: 128-132Google Scholar]. This latter condition is stable over the years, but many patients retain low levels of viremia, as detected by the polymerase chain reaction [[9]Bortolotti F Wirth S Crivellaro C Alberti A Martine U De Moliner L Long term persistence of hepatitis B virus DNA in the serum of children with chronic hepatitis B after hepatitis B e antigen to antibody seroconversion.J Pediatr Gastroenterol Nutr. 1996; 22: 270-274Crossref PubMed Scopus (42) Google Scholar]. This finding is consistent with the possibility of late reactivation of virus replication or with persistence of low grade liver damage, which could be exacerbated in adult life by cofactors such as alcohol and drugs.Severe hepatitis, cirrhosis and HCC, as well as selection of HBV mutants leading to anti-HBe positive hepatitis have been reported in most series, but can be considered infrequent patterns of pediatric HBV infection among both vertically and horizontally infected children [10Bortolotti F Calzia R Cadrobbi P Giacchino R Ciravegna B Armigliato M et al.Liver cirrhosis associated with chronic hepatitis B virus infection in childhood.J Pediatr. 1986; 108: 224-227Abstract Full Text PDF PubMed Scopus (92) Google Scholar, 11Barbera C Calvo P Coscia A Perugini L Dastoli G Randone A et al.Precore mutant hepatitis B virus and outcome of chronic infection and hepatitis in hepatitis B e antigen positive children.Pediatr Res. 1994; 36: 347-350Crossref PubMed Scopus (21) Google Scholar, 12Chung T Tong M.J Hwang B Lee S.D Hu M.M Primary hepatocellular carcinoma and hepatitis B infection during childhood.Hepatology. 1987; 7: 46-48Crossref PubMed Scopus (80) Google Scholar].Taken together, these data indicate that CHB is essentially a mild disease throughout childhood and adolescence, but complications can be expected in adult life, especially among perinatally infected subjects. As a consequence, the rationale for treating children with CHB would be the prevention of late complications rather than the urgent improvement of liver disease. Thus far, the goal of treatment has been to induce or speed the transition from a phase of active virus replication to the inactive carrier state, eventually followed by eradication of infection. The short-term endpoints of treatment have been: HBV DNA clearance (by hybridization techniques), HBeAg loss and subsequent anti-HBe seroconversion, normalization of ALT, improved liver histology, and eventual clearance of HBsAg. At issue is whether a successful treatment may positively influence the outcome of infection in adult life. Interesting results come from long-term controlled studies in adults with HBeAg positive CHB treated with interferon (IFN). Over a follow-up period lasting up to 7–11 years the risk of developing HCC or end-stage liver disease was lower in treated than in untreated patients [13Niederau C Heintges T Lange S Goldmann G Niederau C.M Mohr L Haussinger D Long-term follow-up of HBeAg positive patients treated with interferon alpha for chronic hepatitis B.N Engl J Med. 1996; 334: 1422-1427Crossref PubMed Scopus (800) Google Scholar, 14Lau D.-Y Everhat J Kleiner D.E Park Y Vergalla J Schmid P Hoofnagle J.H Long-term outcome of patients with chronic hepatitis B treated with interferon alpha.Gastroenterology. 1997; 113: 1660-1667Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 15Ikeda K Saitoh S Suzuki Y Kobayashi M Tsubota A Fukuda M et al.Interferon decreases hepatocellular carcinogenesis in patients with cirrhosis caused by the hepatitis B Virus.Cancer. 1998; 82: 827-835Crossref PubMed Scopus (191) Google Scholar]. Given the limited efficacy of the drugs available today, and the mild disease encountered in most pediatric patients, the urgency of treating children with CHB has been questioned [16Huang J Rosenthal P Is Interferon therapy in pediatric chronic hepatitis B infection warranted?.J Pediatr Gastroenterol Nutr. 2000; 31: 217-219Crossref PubMed Scopus (2) Google Scholar, 17Roberts E.A Why to treat chronic hepatitis B in childhood with interferon?.Gut. 2000; 46: 591-593Crossref PubMed Google Scholar]. Rather than discouraging treatment, however, the limits of current therapeutic resources should prompt a revision of the past experience, taking advantage of what we have learned from IFN and lamivudine trials to improve the quality of forthcoming studies.2. IFN: the lesson of clinical trialsThe first therapeutic trials with this immunomodulatory antiviral drug were started in the late 1980s. Since then, a number of papers has been published, regarding different aspects of IFN treatment in children: efficacy in clinical trials, tolerability and side effects, predictors of response and candidacy to treatment, retreatment of non-responders and associations with other drugs as well as cost-benefit of treatment.2.1 EfficacyIFN-α is efficient in accelerating HBeAg clearance and significantly increases the rate of HBsAg clearance. Although many children with CHB have been treated – 1122 cases reported by 18 European groups in 1999 [[18]Jara P Bortolotti F Interferon alpha treatment of chronic hepatitis B in childhood: a consensus advice based on experience in European children.J Pediatr Gastroenterol Nutr. 1999; 29: 163-170Crossref PubMed Scopus (89) Google Scholar] and 1688 recorded in Poland between 1990 and 1997 [[19]Lebensztejn D.M Kaczamarski M Current knowledge on treatment of chronic hepatitis B in children.Med Sci Monit. 2000; 6: 198-2003PubMed Google Scholar] – the evaluation of efficacy relies on few therapeutic trials fulfilling more stringent experimental criteria. We analyzed nine published controlled and randomized studies [20Lai C.L Lok A.S.F Lin H.J Wu P.-C Yeo E.-K Yeung C.-Y Placebo-controlled trial of recombinant alfa2 interferon in Chinese HBsAg carrier children.Lancet. 1987; ii: 877-880Abstract Scopus (172) Google Scholar, 21Lai C.L Lin H.J Lau J.Y.N Lok A.S.F Wu P.-C Chung H.T et al.Effect of recombinant alpha2 interferon with or without prednisone in Chinese HBsAg carrier children.Q J Med. 1991; 286: 155-163Google Scholar, 22Ruiz-Moreno M Jimenes J Porres J.C Bartholomé J Moreno A Carreno V A controlled trial of recombinant interferon alpha in Caucasian children with chronic hepatitis B.Digestion. 1990; 45: 26-33Crossref PubMed Scopus (63) Google Scholar, 23Ruiz-Moreno M Rua M Molina J Moraleda G Moreno A Garcia-Aguado G Carreno V Prospective, randomised, controlled trial of interferon-alpha in children with chronic hepatitis B.Hepatology. 1991; 13: 1035-1039Crossref PubMed Scopus (127) Google Scholar, 24Utili R Sagnelli E Galanti B Aprea L Cesaro G Digilio L et al.Prolonged treatment of children with chronic hepatitis B with recombinant alfa2a interferon: a controlled randomized study.Am J Gastroenterol. 1991; 86: 327-330PubMed Google Scholar, 25Barbera C Bortolotti F Crivellaro C Coscia A Zancan L Nebbia G et al.Recombinant interferon alpha 2a hastens the rate of HBeAg clearance in children with chronic hepatitis B.Hepatology. 1994; 20: 287-290Crossref PubMed Scopus (80) Google Scholar, 26Vajro P Tedesco M Fontanella A De Vincenzo A Vecchione R Ammendola R et al.Prolonged and high dose recombinant interferon alpha 2b alone or after prednisone priming accelerates termination of active viral replication in children with chronic hepatitis B infection.Pediatr Infect Dis J. 1996; 15: 223-231Crossref PubMed Scopus (45) Google Scholar, 27Gregorio G.V Jara P Hierro L Diaz C De La Vega A Vegnente A et al.Lymphoblastoid interferon alpha with or without steroid pretreatment in children with chronic hepatitis B. A multicenter controlled trial.Hepatology. 1996; 23: 700-707Crossref PubMed Google Scholar, 28Sokal M.E Conjeevaram H.S Roberts E.A Alvarez F Bern E.M Goyens P et al.Interferon alpha therapy for chronic hepatitis B in children: a multinational randomized controlled trial.Gastroenterology. 1998; 114: 988-995Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar] with regard to treatment efficacy. HBeAg clearance at the end of follow-up was considered the major endpoint of treatment. Table 1 shows the number of cases, treatment schedule, duration of treatment and of follow-up in each of the trials. Two studies involved exclusively Chinese children [20Lai C.L Lok A.S.F Lin H.J Wu P.-C Yeo E.-K Yeung C.-Y Placebo-controlled trial of recombinant alfa2 interferon in Chinese HBsAg carrier children.Lancet. 1987; ii: 877-880Abstract Scopus (172) Google Scholar, 21Lai C.L Lin H.J Lau J.Y.N Lok A.S.F Wu P.-C Chung H.T et al.Effect of recombinant alpha2 interferon with or without prednisone in Chinese HBsAg carrier children.Q J Med. 1991; 286: 155-163Google Scholar], the remaining series were almost entirely composed of Caucasian patients, while the study by Sokal et al. [[28]Sokal M.E Conjeevaram H.S Roberts E.A Alvarez F Bern E.M Goyens P et al.Interferon alpha therapy for chronic hepatitis B in children: a multinational randomized controlled trial.Gastroenterology. 1998; 114: 988-995Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar] included also black and oriental children. Age ranging between 1.5 and 17 years, and positive HBeAg and HBV DNA were inclusion criteria in all studies. Increased ALT and liver histology were not required in Chinese children with normal ALT. Post-treatment liver biopsy was not available. The heterogeneity of the sample and the methodological limits clearly introduce several biases in the evaluation of these studies. Overall, 465 children either receiving IFN alone (238) or placebo or no treatment (227) were included. Table 2 shows the rate of HBeAg clearance at the end of post-treatment follow-up: the difference between treated and untreated patients (30% vs. 12%) was statistically significant. At the same time HBsAg clearance was recorded in 12/238 treated children, but in 1/227 untreated or placebo-treated children.Table 1Regimens of treatment and follow-up in nine controlled randomized trials of interferon-α in children with chronic hepatitis BFirst author [Ref.]Cases (n)ScheduleDuration of therapyDuration of follow-upaThe duration is the same for all arms of each study.Lai [20]Lai C.L Lok A.S.F Lin H.J Wu P.-C Yeo E.-K Yeung C.-Y Placebo-controlled trial of recombinant alfa2 interferon in Chinese HBsAg carrier children.Lancet. 1987; ii: 877-880Abstract Scopus (172) Google Scholar12IFN (2.5 MU-) 10 MU/m2 TIW12 weeks15 months12PlaceboLai [21]Lai C.L Lin H.J Lau J.Y.N Lok A.S.F Wu P.-C Chung H.T et al.Effect of recombinant alpha2 interferon with or without prednisone in Chinese HBsAg carrier children.Q J Med. 1991; 286: 155-163Google Scholar31PDN×6 weeks+IFN 5 MU/m2 TIW16 weeks18 months29IFN 5 MU/m2 TIW16 weeks30PlaceboRuiz-Moreno [22]Ruiz-Moreno M Jimenes J Porres J.C Bartholomé J Moreno A Carreno V A controlled trial of recombinant interferon alpha in Caucasian children with chronic hepatitis B.Digestion. 1990; 45: 26-33Crossref PubMed Scopus (63) Google Scholar12IFN 10 MU/m2 TIW3 months15 months12UntreatedRuiz-Moreno [23]Ruiz-Moreno M Rua M Molina J Moraleda G Moreno A Garcia-Aguado G Carreno V Prospective, randomised, controlled trial of interferon-alpha in children with chronic hepatitis B.Hepatology. 1991; 13: 1035-1039Crossref PubMed Scopus (127) Google Scholar12IFN 10 MU/m2 TIW6 months9 months12IFN 5 MU/m2 TIW6 months12UntreatedUtili [24]Utili R Sagnelli E Galanti B Aprea L Cesaro G Digilio L et al.Prolonged treatment of children with chronic hepatitis B with recombinant alfa2a interferon: a controlled randomized study.Am J Gastroenterol. 1991; 86: 327-330PubMed Google Scholar10IFN 3 MU/m2 TIW12 months6 months10UntreatedBarbera [25]Barbera C Bortolotti F Crivellaro C Coscia A Zancan L Nebbia G et al.Recombinant interferon alpha 2a hastens the rate of HBeAg clearance in children with chronic hepatitis B.Hepatology. 1994; 20: 287-290Crossref PubMed Scopus (80) Google Scholar21IFN 7.5 MU/m2 TIW6 months12 months19IFN 3 MU/m2 TIW6 months39UntreatedVajro [26]Vajro P Tedesco M Fontanella A De Vincenzo A Vecchione R Ammendola R et al.Prolonged and high dose recombinant interferon alpha 2b alone or after prednisone priming accelerates termination of active viral replication in children with chronic hepatitis B infection.Pediatr Infect Dis J. 1996; 15: 223-231Crossref PubMed Scopus (45) Google Scholar9PDN×6 weeks+IFN 10 MU/m2 TIW12 months12 monthsbFollow up results analyzed at 12 months and at 24 months.13IFN 10 MU/m2 TIW12 months9UntreatedGregorio [27]Gregorio G.V Jara P Hierro L Diaz C De La Vega A Vegnente A et al.Lymphoblastoid interferon alpha with or without steroid pretreatment in children with chronic hepatitis B. A multicenter controlled trial.Hepatology. 1996; 23: 700-707Crossref PubMed Google Scholar34PDN per 4 weeks+IFN 5 MU/m2 TIW12 weeks18 months30Placebo+IFN 5 MU/m2 TIW12 weeks31UntreatedSokal [28]Sokal M.E Conjeevaram H.S Roberts E.A Alvarez F Bern E.M Goyens P et al.Interferon alpha therapy for chronic hepatitis B in children: a multinational randomized controlled trial.Gastroenterology. 1998; 114: 988-995Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar70IFN 6 MU/m2 TIW24 weeks24 weeks74Untreateda The duration is the same for all arms of each study.b Follow up results analyzed at 12 months and at 24 months. Open table in a new tab Table 2Proportion of treated and untreated patients who clear HBeAg at the end of follow-up in the nine controlled randomized IFN trialsFirst author [Ref.]Treated childrenUntreated childrenOR (95% CI)P valueLai [20]Lai C.L Lok A.S.F Lin H.J Wu P.-C Yeo E.-K Yeung C.-Y Placebo-controlled trial of recombinant alfa2 interferon in Chinese HBsAg carrier children.Lancet. 1987; ii: 877-880Abstract Scopus (172) Google Scholar1/121/121.0 (0.0–17.0)0.47Lai [21]Lai C.L Lin H.J Lau J.Y.N Lok A.S.F Wu P.-C Chung H.T et al.Effect of recombinant alpha2 interferon with or without prednisone in Chinese HBsAg carrier children.Q J Med. 1991; 286: 155-163Google Scholar1/290/307.6 (0.1–99.9)0.49Ruiz-Moreno [22]Ruiz-Moreno M Jimenes J Porres J.C Bartholomé J Moreno A Carreno V A controlled trial of recombinant interferon alpha in Caucasian children with chronic hepatitis B.Digestion. 1990; 45: 26-33Crossref PubMed Scopus (63) Google Scholar4/123/121.4 (0.2–8.2)1.00Ruiz-Moreno [23]Ruiz-Moreno M Rua M Molina J Moraleda G Moreno A Garcia-Aguado G Carreno V Prospective, randomised, controlled trial of interferon-alpha in children with chronic hepatitis B.Hepatology. 1991; 13: 1035-1039Crossref PubMed Scopus (127) Google Scholar11/242/123.4 (0.8–14.10.14Utili [24]Utili R Sagnelli E Galanti B Aprea L Cesaro G Digilio L et al.Prolonged treatment of children with chronic hepatitis B with recombinant alfa2a interferon: a controlled randomized study.Am J Gastroenterol. 1991; 86: 327-330PubMed Google Scholar2/101/102.1 (0.1–23.0)1.00Barbera [25]Barbera C Bortolotti F Crivellaro C Coscia A Zancan L Nebbia G et al.Recombinant interferon alpha 2a hastens the rate of HBeAg clearance in children with chronic hepatitis B.Hepatology. 1994; 20: 287-290Crossref PubMed Scopus (80) Google Scholar10/395/372.1 (0.6–6.5)0.18Vajro [26]Vajro P Tedesco M Fontanella A De Vincenzo A Vecchione R Ammendola R et al.Prolonged and high dose recombinant interferon alpha 2b alone or after prednisone priming accelerates termination of active viral replication in children with chronic hepatitis B infection.Pediatr Infect Dis J. 1996; 15: 223-231Crossref PubMed Scopus (45) Google Scholar7/122/94.1 (0.74–22.4)0.10Gregorio [27]Gregorio G.V Jara P Hierro L Diaz C De La Vega A Vegnente A et al.Lymphoblastoid interferon alpha with or without steroid pretreatment in children with chronic hepatitis B. A multicenter controlled trial.Hepatology. 1996; 23: 700-707Crossref PubMed Google Scholar12/305/313.2 (1.1–9.7)0.04Sokal [28]Sokal M.E Conjeevaram H.S Roberts E.A Alvarez F Bern E.M Goyens P et al.Interferon alpha therapy for chronic hepatitis B in children: a multinational randomized controlled trial.Gastroenterology. 1998; 114: 988-995Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar23/708/743.6 (1.6–8.1)0.001Pooled71/23827/2272.9 (1.8–4.6)0.0001Odds ratio (OR) calculated by Peto's meta-analysis [53]Yusuf S Peto R Lewis J Collins R Sleight P Beta blockade during and after myocardial infarction: an overview of the randomized trials.Prog Cardiovasc Dis. 1985; 27: 335-371Abstract Full Text PDF PubMed Scopus (2648) Google Scholar. CI, confidence interval. Open table in a new tab Patients who respond to treatment clearing HBV DNA and HBeAg by the end of post-treatment follow-up are likely to seroconvert to anti-HBe and to normalize ALT during the subsequent months, and to persist in this status thereafter. The medium-term prognosis of infection and disease in children with CHB treated with IFN has been investigated in a series of 107 children from two controlled studies, and compared to that of 59 related controls [28Sokal M.E Conjeevaram H.S Roberts E.A Alvarez F Bern E.M Goyens P et al.Interferon alpha therapy for chronic hepatitis B in children: a multinational randomized controlled trial.Gastroenterology. 1998; 114: 988-995Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 29Bortolotti F Jara P Barbera C Gregorio G.V Vegnente A Zancan L et al.Long-term effect of alpha interferon in children with chronic hepatitis B.Gut. 2000; 46: 715-718Crossref PubMed Scopus (119) Google Scholar]. After 5 years the proportion of treated children with sustained HBeAg clearance was similar in responders and non-responders and did not differ from that of untreated controls. These data suggest that, at least in European children, IFN simply accelerates the spontaneous HBeAg clearance. HBsAg loss, however, was significantly more frequent in treated children who were early responders; thus treatment favors the eradication of infection in this subgroup of patients.2.2 Predictors of responseEpidemiological, clinical, serological and histological criteria supporting the decision to treat or not to treat a child with CHB are highly desirable. The results provided by clinical trials are rather heterogeneous due to the small sample size, the different rate of perinatal infection, and the different duration of follow-up. High ALT levels were significantly associated with response to treatment in three of five controlled randomized trials. On the other hand response to IFN was poor in Chinese children with normal transaminases [20Lai C.L Lok A.S.F Lin H.J Wu P.-C Yeo E.-K Yeung C.-Y Placebo-controlled trial of recombinant alfa2 interferon in Chinese HBsAg carrier children.Lancet. 1987; ii: 877-880Abstract Scopus (172) Google Scholar, 21Lai C.L Lin H.J Lau J.Y.N Lok A.S.F Wu P.-C Chung H.T et al.Effect of recombinant alpha2 interferon with or without prednisone in Chinese HBsAg carrier children.Q J Med. 1991; 286: 155-163Google Scholar]. HBV DNA levels <1000 pg/ml or 80% of cases during the first weeks of treatment. Neutropenia is the most frequent cause for dose reduction. Vegnente et al. [[39]Vegnente A Guida S Di Costanzo V Fusco C Iorio C Toscano P Nutritional status and growth in children with chronic hepatitis B.J Pediatr Gastroenterol Nutr. 1992; 14: 123-127Crossref PubMed Scopus (11) Google Scholar] and Gottrand et al. [[40]Gottrand F Michaud L Guimber B Ategbo S Dubar G Turch D Farriaux J.P Influence of recombinant interferon alpha on nutritional status and growth pattern in children with chronic viral hepatitis.Eur J Pediatr. 1996; 155: 1031-1034Crossref PubMed Scopus (33) Google Scholar] investigated the influence of IFN on the nutritional status of children with CHB and found that weight loss was the rule during therapy. Few months after cessation of IFN, however, weight normalized. Comanor et al. [[41]Comanor L Minor J Conjeevaram H.S Roberts E.A Alvarez F Bern E.M et al.Impact of chronic hepatitis B and interferon alpha therapy on growth of children.J Viral Hepat. 2001; 8: 139-147Crossref PubMed Scopus (41) Google Scholar] showed that children's growth temporarily stopped during IFN treatment, although children with CHB could have a compromised growth even in the absence of treatment.2.5 Cost-benefit analysis of IFN treatmentIFN treatment is expensive. In 1997 Jacques and Olson [[42]Louis-Jaques O Olson A.D Cost-benefit analysis of interferon therapy in children with chronic active hepatitis B.J Pediatr Gastroenterol Nutr. 1997; 24: 25-32Crossref PubMed Scopus (23) Google Scholar] calculated the cost per year of life saved by IFN-α for three cohorts of patients with CHB treated at 2, 12 and 25 years, and concluded that IFN is cost-effective especially in young children because of the low dose required and the long life expectancy. However, the risk of severe complications was calculated applying the annual rates observed in adults, and this could be misleading since the long-term outcome of HBV infection acquired early in life is only partially known.2.6 IFN: current useIn spite of its limits (a min
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